This document provides an overview of guidelines for the management of carotid stenosis. It discusses:
1) Stroke is a major cause of death, with many caused by carotid artery disease. The risk of stroke is directly related to the degree of stenosis.
2) Natural history studies show that the risk of stroke is highest in the first year after symptoms and then declines over time. The risk is higher for more severe stenosis.
3) Early trials demonstrated the benefits of carotid endarterectomy (CEA) in reducing stroke risks compared to medical management alone for symptomatic and some asymptomatic patients.
4) Later trials evaluated carotid angioplasty and stenting (CAS) as an alternative to CEA but
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Guidelines in the management of carotid stenosis
1. Guidelines in the Management of
Carotid Stenosis
Professor Alun H Davies
Academic Section of Vascular Surgery,
Imperial College,
Charing Cross & St Mary’s Hospital,
London
2. Stroke
• Each year 120,000 people suffer
1st stroke
• Within 1 year 33% dead
• 3rd most common cause of
death (UK)
Symptoms due to:
- Critical Stenosis
- Occlusion
- Unstable plaque
3. Aetiology of Stroke
• Ischaemic (80%)
- 75% Carotid territory
- 50% thrombo-embolism of ICA or MCA
- 25% small vessel disease
- 15% cardiac embolus,
- 10% other: Takayasu’s arteritis, FMD
- 15% Vertebrobasillar features
- 10% unknown
• Haemorrhagic (20%)
Under-perform by
2-3 fold CEA/CAS
4. Natural history of severe
symptomatic and asymptomatic
carotid artery stenosis
50
60
70
80
90
100
Golledge J, Greenhalgh RM,
Davies AH. Stroke 2000
6 12 18
Time (months)
Freedom
from
ipsilateral
stroke
(%)
ACAS (60-99%)
ECST symptomless
vessel (70-99%)
ECST (80-99%)
NASCET (70-99%)
5. Life-table analysis of stroke
related to presentation
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Amaurosis
TIA
Transient stroke
Established stroke
Progressive stroke
Crescendo TIA
Avoidance of
stroke (%)
Time (months)
Golledge J, Cuming R, Beattie DK,
Davies AH, Greenhalgh RM JVS 1996
6. Life-table analysis of survival
related to presenting symptom
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
Amaurosis
TIA
Transient stroke
Established stroke
Progressive stroke
Crescendo TIA
Survival (%)
Time (months)
Golledge J, Cuming R, Beattie DK,
Davies AH, Greenhalgh RM
JVS 1996
7. Stroke Risk: NASCET and ECST
• 13.1% major ipsilateral stroke at 2 years
• 13%/yr for ANY ipsilateral stroke
• ECST - 16.2% for ANY ipsilateral stroke at
3 years
• Most strokes occur within first year of
signal event
• Risk is directly proportional to degree
of stenosis
Stroke, 1999
8. 30 Day stoke and death rates following
carotid surgery at Charing Cross (CX)
and Leicester Royal Infirmary (L)
0
1
2
3
4
5
Pre 1996 1996-2000
C
X
C
X
L
L
Number 460 494 291 500 823
%
2001-8
12. Natural history - stroke rate in
asymptomatic carotid artery
stenosis
Patients with <75% stenosis - annual
stroke rate 1.3%
Patients with >75% stenosis - annual
stroke rate 3.3%
Chambers BR, Norris JW Stroke 1991
13. Asymptomatic Disease
• Stroke risk with asymptomatic stenosis
(NASCET)
> 60% is 9.9% at 5 yrs
< 60% risk stroke 5.4% at 5 yrs
• ACST : DEGREE OF STENOSIS
60%-80% = 9.5% risk stroke at 5 yrs
80%-99% = 9.6% risk stroke at 5 yrs
• NO INCREASE IN STROKE WITH
INCREASE IN STENOSIS
• THEREFORE There is NO high risk
subgroup of asymptomatic patients based
on degree of stenosis
17. Single center studies 1990-
1999
Studies Number of arteries
PTA 13 714
Endarterectomy 20 6970
Stent used in 44% of patients with cerebral
protection in 11%
Technical failure in 37 Cases (7%)
Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
18. 30 Day Stroke or Death Rate
0
1
2
3
4
5
6
7
8
9
Angioplasty
Endarterectomy
Any stroke
or death
Disabling stroke
or death
%
Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
19. Odds ratio for outcome
Any stroke
Disabling or fatal stroke
TIA
Death
Any stroke or death
Disabling stroke or death
1 2 3 4 5 6 70
Relative odds
2.22
2.09
4.02
0.68
Surgery Angioplasty
Golledge J, Mitchell A, Greenhalgh RM, Davies AH Stroke 2000
20. CAVATAS
CAVATAS trial compared carotid
endarterectomy with carotid
angioplasty.
The rate of any stroke lasting more
than
7 days, or death were 9.9% and
10% respectively. CAVATAS investigators
Lancet June 2001
22. EVAS -3
• RCT
• N=527
Stoke/Death Rates
• 30 day CEA 1.5 % vs CAS 3.4% RR 2.2
• 6/12 CEA 6.1% vs CAS 11.7% p<0.02
• 4 yrs CEA 6.2% vs CAS 11.1% RR 1.97
p<0.03
Mas et al, 2006 ,2008
23. SPACE Trial
• n=1200
• CAS n=605 or CEA n=595
• 30 days CAS 6.84% vs CEA 6.34%
SPACE failed to prove non-inferiority of CAS compared
to CEA. Results do not justify the widespread use in the
short term of CAS for treatment of carotid- artery
stenosis. Reingleb et al 2006
The incidence of recurrent carotid stenosis at 2 years,
as defined by ultrasound, is significantly higher after carotid
artery stenting. Older patients do worse with CAS.
Eckstein et al 2008
24. Carotid endarterectomy was performed with lower
stroke and death rates than carotid artery stenting
in the USA in 2003 and 2004
• During the calendar years 2003 and 2004, an estimated
259,080 carotid revascularization procedures were
performed in the United States. CAS had a higher rate of
in-hospital postoperative stroke (2.1% vs 0.88%, P < .
0001) and higher postoperative mortality (1.3% vs
0.39%) than CEA.
• For symptomatic patients (8%), the rates for
postoperative stroke (4.2% vs 1.1%, P < .0001) and
mortality (7.5% vs 1.0%, P < .0001) were significantly
higher after CAS
McPhee et al, 2007
25. Clinical results of carotid artery stenting
compared with carotid endarterectomy
• Ten trials encompassing 3580 patients were analyzed.
Patients who underwent CAS had a higher risk of 30-day
stroke/death relative to patients who underwent CEA
(risk ratio [RR], 1.30; 95% CI, 1.01-1.67).
• Subgroup analysis of trials enrolling only symptomatic
patients showed higher risk of 30-day stroke/death (RR,
1.63; 95% CI, 1.18-2.25), but trials enrolling both
symptomatic and asymptomatic patients showed no
significant differences (RR, 0.89; 95% CI, 0.59-1.35).
Brahmandam et al 2008
26. Risk-adjusted 30-day outcomes of carotid stenting
and endarterectomy: results from the
SVS Vascular Registry.
• When CAS and CEA were compared in the treatment of
atherosclerotic disease only, the difference in outcomes between
the two procedures was more pronounced, with death/stroke/MI
6.42% after CAS vs 2.62% following CEA, P < .0001.
• Following best possible risk adjustment of these
unmatched groups, symptomatic and asymptomatic CAS
patients had significantly higher 30-day postprocedure
incidence of death/stroke/MI when compared with CEA
patients.
Sidway et al 2009
27. Further on Going Trials
• Various RCTs on CEA vs PTA + Stent
CAVATAS II
ACST II
TACIT
SPACE II
Equipoise!
28. Timing of Angioplasty
Many suggest wait 6 weeks
Assuming similar stroke rate CEA still prevents
170 more strokes per 1000 interventions
33. CREST Study Design
• RCT of CAS vs CEA
• 1:1 randomisation, stratified by centre and
symptomatic status
• Lead-in credentialing for CAS
– N=20 CAS
– 427 applicants, 224 (52%) approved to randomise
• Primary end-point – composite:
– Any stroke, MI (including biochemical) or death within
30 days
– Ipsilateral stroke to 4 years
• Target recruitment 2,500
• Industry sponsored
37. CREST
• symptomatic (n=1,321) or asymptomatic (n=1,181)
• At 30 days, the rate of stroke was significantly higher with stenting,
at 4.1% vs. 2.3% with surgery.
• Myocardial infarction was higher with carotid endarterectomy, at
2.3% vs. 1.1% with stenting.
• when death and stroke are considered alone, there are almost twice
as many events with carotid stenting/angioplasty as there are with
carotid endarterectomy.
“I do not believe the results of CREST should alter the conclusion
that endarterectomy remains the treatment of choice for
symptomatic patients”
Moore 2010, PI CREST
38. CREST Limitations
• Composite endpoint
• Biochemical MI
• Underpowered to show difference in death and major
ipsilateral stroke
• Heterogeneity of symptomatic and asymptomatic patients
• Not all patients on statins
• More lipid lowering in CEA
• More anti-platelets in CAS
• Advances in BMT, CEA stent and embolic protection
since CREST commenced in 2000
• Can CREST CAS results be reproduced in wider
practice?
• Left to interpretation based on personal bias?
39. Identify at risk asymptomatic
patients
• NNT
• Degree of stenosis
• Plaque type
48. Results
-0.1 0.1 0.2
-2000
2000
4000
6000
£20, 000 per QALY
£30, 000 per QALY
Women > 75y
Men > 75y
Men < 75y
Women < 75y
BASE CASE
CEA more costly
CEA more effective
Restriction of crossovers
Incremental effectiveness / QALYs
Incrementalcost/£
Base case ICER
= £7584/QALY
50. Limitations
• Previous US trials with higher stroke rates, shorter follow
up and fewer patients excluded
• TIA not included as endpoint
• Loss of productivity from stroke not included in costs
• Informal care not included in costs
• Stenting not considered following interim guidance from
NICE
51. Interpretation
• Endarterectomy was likely to be cost-effective in under 75s
• Especially so in young women
• Late crossovers to endarterectomy did not improve cost-
effectiveness
• With lower background stroke rates, endarterectomy may soon
become borderline cost-effective, even if it becomes safer
• Maintaining cost-effectiveness relies on:
• Identification of patients with high risk carotid plaque
• Maintaining low rates of operative stroke
• Prevention of cardiac death for men in their 70s
The natural histories of equally severe symptomatic and asymptomatic carotid artery stenosis are different
This data showing freedom from stroke from the medical arm of the NASCET/ACAS and ECST trials demonstrates this.
This suggests a dicotomy in plaque behavior
We perform 1000 asymptomatic CEAs in the UK every year with an annual cost of approximately £3.5 m.
Carotid stenosis is common found in 2-7% of the population over 60.
ACST – European, 10 year follow, most contemporary medical therapy, large dataset
Survival after stoke used appropriate UK literature
Using the concept of incremental costs and incremental effects we define the cost-effectiveness plane.
We use this to illustrate the relative cost and effect of an intervention compared to some control.
If the intervention lies in the south-east quadrant, it is both less expensive and more effective than the control, and so will be preferred.
In the north-west quadrant, an intervention is more expensive and less effective, and so the control will be preferred.
In the other two quadrants there is a trade-off between cost and effectiveness.
The ICER is illustrated by the slope of a line through the origin and the IE/IC point for an intervention.
Compare this with the ‘threshold’ cost-effectiveness ratio – assume around £20,000 to £30,000 per QALY for NICE decisions.
Explain axes
To be cost-effective the data point should lie under the line.
Probability of base case being cost-effective at a £30 000 cost per QALY was 84%.
Sensitivity analysis determined that CEA was unlikely to be cost-effective in those over 75 years of age
In ACST young women had the greatest relative risk reduction with CEA due to the lowest intercurrent mortality and CEA was especially beneficial in this group.
Restricting crossover mainly towards late CEA in elderly patients did not improve cost-effectiveness as CEA (per protocol).
For women over 75 the subgroup was too small to establish effectiveness with any certainty.
For women under 75 CEA was especially effective and life expectancy was longest making this especially cost-effective.
Base case ICER £7500 k
Men under 75 £3500 k
Men over 75 ICER £72 k
Women under 75 negative ICER
Restriction of crossovers £10 149
Explain axes
The more cost-effective an intervention is the higher it is up the page
CREST
ACES/Spence/Abbott/SMART
These assumptions are all conservative assumptions and probably make early CEA more cost-effective
Late crossovers (per protocol)
However as we know, carotid stenosis and stroke become more common in patients over 75. The use of an age cutoff may in fact miss many of the patients with carotid stenosis who are at high risk of stroke. An alternative approach would be to look at the risk of stroke.
Interpretation
Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.
Among patients undergoing carotid revascularization, CAS is associated with better HRQOL during the early recovery period as compared with CEA—particularly with regard to physical limitations and pain—but these differences diminish over time and are not evident after 1 year. Although CAS and CEA are associated with similar overall HRQOL at 1 year, event-specific analyses confirm that stroke has a greater and more sustained impact on HRQOL than MI.
There were no significant differences between CAS versus CEA by symptomatic status for the primary CREST end point.
Periprocedural stroke and death rates were significantly lower for CEA in symptomatic patients.
